Telaprevir may induce adverse cutaneous reactions by a T cell immune-mediated mechanism.

The HCV protease inhibitor telaprevir associated with peginterferon-alpha and ribavirin, was widely used in the recent past as standard treatment in HCV genotype-1 infected patients. Telaprevir improves the sustained virology response rates, but at the same time increases the frequency of adverse cutaneous reactions. However, mechanisms through which telaprevir induces cutaneous lesions are not yet defined. A 50-year-old woman, affected by HCV genotype 1b, was admitted to our Department for a telaprevir-related severe cutaneous eruptions, eight weeks after starting a triple therapy (telaprevir associated with Peginterferon-alpha and ribavirin). Mechanisms of cutaneous reactions were investigated by skin tests with non-irritating concentrations of telaprevir and by activating in vitro T lymphocyte with different concentrations. Immediate and delayed responses to skin testing were negative, but the drug-induced lymphocytes activation was significantly higher as compared to patient's baseline values and to parallel results obtained in three healthy subjects (p < 0.05). In conclusion, adverse cutaneous reactions of our patient were caused by a telaprevir-induced T-cell dependent immune mechanism.

Urotensin-II receptor is over-expressed in colon cancer cell lines and in colon carcinoma in humans.

BACKGROUND: Urotensin (U)-II receptor (UTR) has been previously reported to be over-expressed in a number of tumours. Whether UTR-related pathway plays a role in colon carcinogenesis is unknown. METHODS: We evaluated UTR protein and mRNA expression in human epithelial colon cancer cell lines and in normal colon tissue, adenomatous polyps and colon cancer. U-II protein expression was assessed in cancer cell lines. Moreover, we evaluated the effects of U-II(4-11) (an UTR agonist), antagonists and knockdown of UTR protein expression through a specific shRNA, on proliferation, invasion and motility of human colon cancer cells. RESULTS: Cancer cell lines expressed U-II protein and UTR protein and mRNA. By immunohistochemistry, UTR was expressed in 5-30% of epithelial cells in 45 normal controls, in 30-48% in 21 adenomatous polyps and in 65-90% in 48 colon adenocarcinomas. UTR mRNA expression was increased by threefold in adenomatous polyps and eightfold in colon cancer, compared with normal colon. U-II(4-11) induced a 20-40% increase in cell growth while the blockade of the receptor with specific antagonists caused growth inhibition of 20-40%. Moreover, the knock down of UTR with a shRNA or the inhibition of UTR with the antagonist urantide induced an approximately 50% inhibition of both motility and invasion. CONCLUSIONS: UTR appears to be involved in the regulation of colon cancer cell invasion and motility. These data suggest that UTR-related pathway may play a role in colon carcinogenesis and that UTR may function as a target for therapeutic intervention in colon cancer.

New silibinin glyco-conjugates: synthesis and evaluation of antioxidant properties.

New silibinin glyco-conjugates have been synthesized by efficient method and in short time. Exploiting our solution phase strategy, several structurally diverse silibinin glyco-conjugates (gluco, manno, galacto, and lacto-) were successfully realized in very good yields and in short time. In preliminary study to evaluate their antioxidant and neuroprotective activities new derivatives were subjected to DPPH free radical scavenging assay and the Xanthine oxidase (XO) inhibition models assay. Irrespective of the sugar moiety examined, new glyco-conjugates are more than 50 times water-soluble of silibinin. In the other hand they exhibit a radical scavenging activities slightly higher than to silibinin and XO inhibition at least as silibinin.

Symbiotic formulation in experimentally induced liver fibrosis in rats: intestinal microbiota as a key point to treat liver damage?

AIM: Evidence indicates that intestinal microbiota may participate in both the induction and the progression of liver damage. The aim of our research was the detection and evaluation of the effects of chronic treatment with a symbiotic formulation on CCl4 -induced rat liver fibrosis. RESULTS: CCl4 significantly increased gastric permeability in respect to basal values, and the treatment with symbiotic significantly decreased it. CCl4 per se induced a decrease in intestinal permeability. This effect was also seen in fibrotic rats treated with symbiotic and was still evident when normal rats were treated with symbiotic alone (P < 0.001 in all cases). Circulating levels of pro-inflammatory cytokine TNF-α were significantly increased in rats with liver fibrosis as compared with normal rats, while symbiotic treatment normalized the plasma levels of TNF-α and significantly enhanced anti-inflammatory cytokine IL 10. TNF-α, TGF-ß, TLR4, TLR2, iNOS and α-SMA mRNA expression in the liver were up-regulated in rats with CCl4 -induced liver fibrosis and down-regulated by symbiotic treatment. Moreover, IL-10 and eNOS mRNA levels were increased in the CCL4 (+) symbiotic group. Symbiotic treatment of fibrotic rats normalized serum ALT, AST and improved histology and liver collagen deposition. DGGE analysis of faecal samples revealed that CCl4 administration and symbiotic treatment either alone or in combination produced modifications in faecal profiles vs controls. CONCLUSIONS: Our results provide evidence that in CCl4 -induced liver fibrosis, significant changes in gastro-intestinal permeability and in faecal flora occur. Treatment with a specific symbiotic formulation significantly affects these changes, leading to improvement in both liver inflammation and fibrosis.

Interaction of alcohol intake and cofactors on the risk of cirrhosis.

OBJECTIVE: Evaluation of the interaction between alcohol intake and cofactors [hepatitis B virus (HBV), hepatitis C virus (HCV), body mass index] and coffee consumption on the risk of cirrhosis. DESIGN: Seven hundred and forty-nine consecutive patients with chronic liver disease referring to units for liver or alcohol diseases in Italy during a 6-months period. Teetotalers were excluded. The odds ratios (OR) for cirrhosis were evaluated using chronic hepatitis cases as the control group. RESULTS: An alcohol intake of more than 3 units/day resulted associated with the likelihood of cirrhosis both in males (OR 4.3; 95% CI=2.5-7.3) and in females (OR 5.7; 95% CI=2.3-14.5). A multiplicative interaction on the risk of cirrhosis between risky alcohol intake and HBsAg or HCV-Ab/HCV-RNA positivity was observed. A reduction of cirrhosis risk was observed in subjects consuming more than 3 alcohol units/day with increasing coffee intake. The OR for the association with cirrhosis decreased from 2.3 (95% CI=1.2-4.4) in subjects drinking 0-2 cups of coffee/day to 1.4 (95% CI=0.6-3.6) in those drinking more than 2 cups/day. CONCLUSIONS: In subjects with an alcohol intake >3 units/day the coexistence of HBV or HCV multiplies the risk of cirrhosis. Coffee represents a modulator of alcoholic cirrhosis risk.

Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study.

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive disorder of the urea cycle. With the exception of the French-Canadian founder effect, no common mutation has been detected in other populations. In this study, we collected 16 additional HHH cases and expanded the spectrum of SLC25A15/ORC1 mutations. Eleven novel mutations were identified including six new missense and one microrearrangement. We also measured the transport properties of the recombinant purified proteins in reconstituted liposomes for four new and two previously reported missense mutations and proved that the transport activities of these mutant forms of ORC1 were reduced as compared with the wild-type protein; residual activity ranged between 4% and 19%. Furthermore, we designed three-dimensional (3D)-modeling of mutant ORC1 proteins. While modeling the changes in silico allowed us to obtain new information on the pathomechanisms underlying HHH syndrome, we found no clear-cut genotype-phenotype correlations. Although patient metabolic alterations responded well to low-protein therapy, predictions concerning the long-term evolution of HHH syndrome remain uncertain. The preference for a hepatic rather than a neurological presentation at onset also continues, largely, to elude us. Neither modifications in oxidative metabolism-related energy, such as those expected in different mtDNA haplogroups, nor sequence variants in SLC25A2/ORC2 seem to be crucial. Other factors, including protein stability and function, and ORC1-ORC2 structural interactions should be further investigated.

Silybin, a component of sylimarin, exerts anti-inflammatory and anti-fibrogenic effects on human hepatic stellate cells.

BACKGROUND/AIMS: Hepatic fibrogenesis, a consequence of chronic liver tissue damage, is characterized by activation of the hepatic stellate cells (HSC). Silybin has been shown to exert anti-fibrogenic effects in animal models. However, scant information is available on the fine cellular and molecular events responsible for this effect. The aim of this study was to assess the mechanisms regulating the anti-fibrogenic and anti-inflammatory activity of Silybin. METHODS: Experiments were performed on HSC isolated from human liver and activated by culture on plastic. RESULTS: Silybin was able to inhibit dose-dependently (25-50 microM) growth factor-induced pro-fibrogenic actions of activated human HSC, including cell proliferation (P < 0.001), cell motility (P < 0.001), and de novo synthesis of extracellular matrix components (P < 0.05). Silybin (25-50 microM), inhibited the IL-1-induced synthesis of MCP-1 (P < 0.01) and IL-8 (P < 0.01) showing a potent anti-inflammatory activity. Silybin exerts its effects by directly inhibiting the ERK, MEK and Raf phosphorylation, reducing the activation of NHE1 (Na+/H+ exchanger, P < 0.05) and the IkBalpha phosphorylation. In addition, Silybin was confirmed to act as a potent anti-oxidant agent. CONCLUSION: The results of the study provide molecular insights into the potential therapeutic action of Silybin in chronic liver disease. This action seems to be mostly related to a marked inhibition of the production of pro-inflammatory cytokines, a clear anti-oxidant effect and a reduction of the direct and indirect pro-fibrogenic potential of HSC.

Hepatic encephalopathy 2018: A clinical practice guideline by the Italian Association for the Study of the Liver (AISF).

Hepatic encephalopathy (HE) is a common, worrisome and sometimes difficult to manage complication of end-stage liver disease. HE is often recurrent, requiring multiple hospital admissions. It can have serious implications in terms of a patient's ability to perform complex tasks (for example driving), their earning capacity, their social and family roles. This guideline reviews current knowledge on HE definition, pathophysiology, diagnosis and treatment, both by general principles and by way of a summary of available drugs and treatment strategies. The quality of the published, pertinent evidence is graded, and practical recommendations are made. Where possible, these are placed within the Italian health service context, with reference to local diagnosis and management experience.

The impact of diet on liver fibrosis and on response to interferon therapy in patients with HCV-related chronic hepatitis.

BACKGROUND AND AIMS: A deranged metabolic status and alcohol intake may trigger induction and progression of chronic hepatitis C virus (HCV) liver disease. The aim of this study was to evaluate whether dietary composition affects the severity of liver damage and response to therapy in patients with HCV-related chronic hepatitis. METHODS: We enrolled 1,084 patients with biopsy-proven HCV-related chronic hepatitis (432 treated with interferon plus ribavirin) and 2,326 healthy subjects in this prospective study conducted in a university hospital. Dietary habits were recorded in enrolled individuals, and their alcohol consumption was evaluated with a questionnaire (AUDIT). Body mass index, and plasma levels of blood glucose, nitrogen, creatinine, cholesterol, and triglycerides were also measured. All individuals underwent routine liver tests and HCV genotyping. RESULTS: At study onset, there were no differences in metabolic status or alcohol consumption between patients and controls. About 50% of each group was overweight, and about 60% consumed alcohol. Patients and controls had similar dietary habits. Intake of carbohydrates, lipids and polyunsaturated fatty acids, and alcohol consumption were independent factors of liver damage at histology (logistic regression analysis). Some dietary components (unsaturated fatty acids, iron, zinc, vitamin A, and niacin) and alcohol intake differed significantly (P < 0.05 and P 0.01, respectively; univariate analysis) between responders and nonresponders to interferon therapy. Genotype, age, body mass index, steatosis, and fibrosis were independent predictors of therapy outcome (P < 0.02; multivariate analysis). CONCLUSIONS: The severity of HCV-related chronic hepatitis depends on a variety of factors. Our results show that dietary composition is related to the extent of liver damage. Although traditional risk factors independently affected treatment response, some dietary components were associated with nonresponse to therapy in our patients. This suggests that HCV patients may benefit from instructions regarding their diet.

Emerging drugs for non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a condition of emerging relevance that includes different forms of chronic liver damage, from a simple fatty infiltration (steatosis) of hepatocytes to steatohepatitis (NASH) with fibrosis. This last form may evolve to cirrhosis and hepatocellular carcinoma. OBJECTIVE: To discuss therapeutic management of NAFLD. Theoretically, only patients with non-alcoholic steatohepatitis (NASH) need to be treated, as only NASH may evolve to cirrhosis. Differentiation between steatosis and NASH currently requires a liver biopsy. METHODS: We discuss different therapeutic approaches proposed in literature for patients with NAFLD. RESULTS: The treatment of associated conditions leads to an improvement of NAFLD and NASH. No specific drug is actually present to treat liver steatosis or NASH. CONCLUSIONS: The treatment of NAFLD depends on the individual characteristics of each patient. Diet and physical exercise may be considered a basal universal approach. Future research will discover possible specific liver drugs.

Chronic inflammation and oxidative stress in human carcinogenesis.

A wide array of chronic inflammatory conditions predispose susceptible cells to neoplastic transformation. In general, the longer the inflammation persists, the higher the risk of cancer. A mutated cell is a sine qua non for carcinogenesis. Inflammatory processes may induce DNA mutations in cells via oxidative/nitrosative stress. This condition occurs when the generation of free radicals and active intermediates in a system exceeds the system's ability to neutralize and eliminate them. Inflammatory cells and cancer cells themselves produce free radicals and soluble mediators such as metabolites of arachidonic acid, cytokines and chemokines, which act by further producing reactive species. These, in turn, strongly recruit inflammatory cells in a vicious circle. Reactive intermediates of oxygen and nitrogen may directly oxidize DNA, or may interfere with mechanisms of DNA repair. These reactive substances may also rapidly react with proteins, carbohydrates and lipids, and the derivative products may induce a high perturbation in the intracellular and intercellular homeostasis, until DNA mutation. The main substances that link inflammation to cancer via oxidative/nitrosative stress are prostaglandins and cytokines. The effectors are represented by an imbalance between pro-oxidant and antioxidant enzyme activities (lipoxygenase, cyclooxygenase and phospholipid hydroperoxide glutathione-peroxidase), hydroperoxides and lipoperoxides, aldehydes and peroxinitrite. This review focalizes some of these intricate events by discussing the relationships occurring among oxidative/nitrosative/metabolic stress, inflammation and cancer.

Gut microbiota and the liver.

Nowadays liver diseases represent one of major healthy problems in the world in terms of morbidity and mortality. The high prevalence of liver pathologies represents the key point to understand the necessity to identify the pathogenetic mechanisms that support these disorders in order to nurse them. Alterations of intestinal microbiota seem to play an important role in induction and promotion of liver damage progression, in addition to direct injury resulting from different causal agents. Gut microbiota is considered both as a promoting factor and as a potential therapeutic target of a large number of liver pathologies due to the connection between intestine and liver: the gut-liver axis. This connection influences absorption and deposition of nutrients into the liver, but also induces the activation of toll-like receptors due to the passage of pathogen-associated molecular patterns in the portal blood and therefore may start both the development of liver damage and its consequent progression to more advanced stages, including cirrhosis and hepatocarcinoma. The gut liver axis also includes the intestinal permeability (IP) degree. It is very variable and interconnected to several factors, most of them dependent from gut microbiota, that is the "lead" in the control of IP. This revue is aimed to report the more recent knowledges about gut microbiota and chronic liver disease, from liver steatosis to cirrhosis and its complications, including hepatocellular carcinoma. For these reasons, it could be useful to intervene, through suitable therapeutic approaches, on the interruption of mechanisms that underlie dysbiosis, IP increase, activation of liver inflammasome, hepatic stellate cells and hepatocarcinogenic processes in order to reduce the liver damage.

Qualitative and Quantitative Evaluation of Dietary Intake in Patients with Non-Alcoholic Steatohepatitis.

There are very few reports about the intake of nutrients for the development or progression of non-alcoholic steatohepatitis (NASH). The aim of this study was to identify the dietary habits and the nutrient intake in patients with NASH, in comparison to chronic hepatitis C (HCV)-related patients. We prospectively evaluated the intake of macronutrients and micronutrients in 124 NAFLD and 162 HCV patients, compared to 2326 subjects as a control group. We noticed major differences in macro- and micronutrients intakes in NASH and HCV patients compared to controls. Proteins, carbohydrate (glucose, fructose, sucrose, maltose and amide), saturated fatty acid (SFA), monounsaturated fatty acid (MUFA), folic acid, vitamin A and C (p < 0.0001), and thiamine (p < 0.0003) ingestion was found to be higher in patients with NASH, while total lipids, polyunsaturated fatty acid (PUFA), riboflavin and vitamin B6 daily intake were lower compared to controls (p < 0.0001). Similarly, NASH patients had significantly reduced carbohydrate intake (p < 0.0001) and an increased intake of calcium (p < 0.0001) compared to HCV positive patients. Finally, we showed in NASH males an increase in the intake of SFA, PUFA, soluble carbohydrates (p < 0.0001) and a decrease in the amount of fiber (p < 0.0001) compared to control males. In NASH female population, we showed an increase of daily total calories, SFA, MUFA, soluble carbohydrates, starch and vitamin D ingested (p < 0.0001) with a reduction of fibers and calcium (p < 0.0001) compared to control females. This study showed how NASH patients' diets, in both male and females, is affected by a profound alteration in macro- and micronutrients intake.

Urotensin-II Receptor: A Double Identity Receptor Involved in Vasoconstriction and in the Development of Digestive Tract Cancers and other Tumors.

Urotensin II and Urotensin-II receptors are important molecular factors that regulate vasoconstriction and all the diseases that are linked to abnormalities in blood pressure regulation (i.e.: hypertension, kidney diseases, cirrhosis etc.). Recently, Urotensin II and its receptor have also been involved in metabolic syndrome, diabetes and schizophrenia. Recent strong findings suggest that Urotensin II and its receptor are involved in the onset and development of different epithelial cancers. Indeed, it was reported that cell growth, motility and invasion in human breast, bladder, prostate, colorectal and glioblastoma cancer cells were regulated by Urotensin II and Urotensin-II receptor axis. This axis also regulated focal adhesion kinase and small Guanosine-5'-triphosphate binding proteins that likely had a role in motility and invasion mediated by Urotensin-II receptor. Additionally, its expression on tumour tissues is variably associated to the prediction of the clinical outcome of the patients and it can be considered an alternative molecular marker to be used as prognostic factor in human cancers. In conclusion, a new weapon in the treatment of human cancers is highlighting a new scenario for the future.

Endocan Serum Levels in Patients with Non-Alcoholic Fatty Liver Disease with or without Type 2 Diabetes Mellitus: A Pilot Study.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is emerging as an independent cardiovascular risk factor. Recently, Endocan has been studied as an early marker of endothelial dysfunction. Our aim was to evaluate Endocan serum levels in patients with NAFLD with or without type 2 diabetes mellitus. METHOD: We enrolled 56 patients: 19 with NAFLD and 37 with type 2 diabetes mellitus with or without NAFLD, and compared them to 25 healthy controls. Endocan serum level was measured by using the ELISA EndoMark assay. RESULTS: Endocan level was significantly higher in NAFLD subjects, compared to controls (1.23+/-1.51 vs 0.68+/-0.4 ng/mL; p=0.016). It was higher in patients with non-alcoholic fatty liver and non-alcoholic steatohepatitis (NASH) (1.12+/-1.11, 1.49+/-2.16 and 0.68+/-0.4 ng/ml vs controls, respectively), independently from presence of type 2 diabetes mellitus. The increase was more marked in patients with NASH and in those with NAFL versus controls (p=0.001 and p=0.004, respectively), but not statistically different between the two groups (p=0.448). Finally, we found a statistically relevant increase of this marker in diabetic NAFLD patients compared to those non diabetic (1.56+/-0.81 vs 0.72+/-0.58 ng/ml; p=0.01). CONCLUSION: We demonstrated an increased Endocan serum level in NAFLD patients, higher in those with type 2 diabetes mellitus and/or NASH because of an endothelial dysfunction in these pathologies.

Reactivation of hepatitis B virus in cancer patients treated with chemotherapy for solid tumors. Is the prophylaxis really required?

BACKGROUND: Reactivation of hepatitis B virus during cancer chemotherapy for non-hematological tumors is not fully clear. AIM: To evaluate the risk of hepatitis B virus reactivation in carriers of hepatitis B virus cancer patients treated with chemotherapy for solid tumors. METHODS: Two hundred sixty-seven patients with solid tumors were consecutively enrolled: 13 (4.8%) were hepatitis B s-antigen positive, of whom 6 were documented inactive carriers and 7 had chronic liver disease. Thirty-two patients (12%) were hepatitis B s-antigen negative/hepatitis B c-antibody positive. Hepatitis B virus inactive carriers were followed every 3 months by alanine aminotransferases, hepatitis B virus-DNA; whereas hepatitis B virus occult carriers were followed every 3 months by alanine aminotransferases and hepatitis B s-antigen. RESULTS: None of the 38 total patients with inactive or occult B infection who did not receive prophylaxis presented hepatitis B virus reactivation during the follow-up period. CONCLUSION: This study suggests that, in hepatitis B s-antigen negative patients who undergo chemotherapy for solid tumors, hepatitis B and c-antibody screening results are not relevant to clinical decision and can be avoided. Larger studies are needed to establish whether the risk of reactivation of HBV during chemotherapy is negligible in this subset of patients and they could not be monitored for HBV reactivation.

Targeting gut-liver axis for the treatment of nonalcoholic steatohepatitis: translational and clinical evidence.

Nonalcoholic fatty liver disease (NAFLD) is widely emerging as the most prevalent liver disorder and is associated with increased risk of liver-related and cardiovascular mortality. Recent experimental and clinical studies have revealed the pivotal role played by the alteration of gut-liver axis in the onset of fatty liver and related metabolic disturbances. Gut-liver cross talk is implicated not only in the impairment of lipid and glucose homeostasis leading to steatogenesis, but also in the initiation of inflammation and fibrogenesis, which characterize nonalcoholic steatohepatitis (NASH), the evolving form of NAFLD. The gut microbiota has been recognized as the key player in the gut-liver liaison and because of its complexity can act as a villain or a victim. Gut microbiota not only influences absorption and disposal of nutrients to the liver, but also conditions hepatic inflammation by supplying toll-like receptor ligands, which can stimulate liver cells to produce proinflammatory cytokines. Thus, the modification of intestinal bacterial flora by specific probiotics has been proposed as a therapeutic approach for the treatment of NASH. In this review, we summarized the evidence regarding the role of gut-liver axis in the pathogenesis of NASH and discussed the potential therapeutic role of gut microbiota modulation in the clinical setting.

Alcoholic Hepatitis: Pathogenesis, Diagnosis and Treatment.

Alcohol represents the oldest substance of abuse known and Alcoholic Liver Disease (ALD) is the most common cause of chronic liver disease worldwide. The ALD includes a wide spectrum of injury and may lead progressively from simple steatosis to frank cirrhosis. The ALD diagnosis may be hard and it is mainly defined by the history of chronic alcohol intake, physical and laboratory abnormalities suggestive of liver disease. Abstinence is the cornerstone of ALD therapy. Although the burden on health of ALD is not negligible, in the last decades few therapeutic advances have been made. Because of the complex pathogenetic mechanisms, the therapy of ALD and especially of severe Alcoholic Hepatitis (AH), represents a thorny problem in the clinical practice. In severe forms of acute AH, some specific drug treatments, including glucorticoids or pentoxifylline, have been defined and are, at the moment, recommended by international guidelines. On the contrary, specific long-term treatments of ALD, aimed at stopping the progression of fibrosis, are not yet approved.

Alcoholic Liver Disease and Hepatitis C Chronic Infection.

Alcoholic and virus C hepatitis currently represent the main causes of chronic liver disease worldwide. Every year many people die and are subjected to complex hospitalization and medical assistance due to these pathologies. Alcoholic liver disease and hepatitis C virus chronic infection are often present in the same patient. These two pathologies sinergically act in determining the onset and progression of liver damage that, from the chronic hepatitis staging, may rapidly progress to fibrosis, cirrhosis and hepatocellular carcinoma. In this review we analysed physiopathological aspects and biomolecular interactions that relate ethanol and hepatitis C virus in determining liver damage; moreover we took into account the effect on the natural history of liver disease deriving from the co-presence of these pathologies. Therefore we paid particular attention to the ability of ethanol and hepatitis C virus to in inducing oxidative stress or lipid accumulation, and analyzed the basic mechanisms of fibrogenesis that both diseases have got, amplified by their co-presence in the same patient. Finally we paid attention to the oncogenetic mechanisms inducing hepatocellular carcinoma and variability of response to antiviral therapy that derives from alcohol abuse in a subject affected by C hepatitis.

Epidemiology and Natural History of Alcoholic Liver Disease.

Alcohol represents the oldest substance of abuse known, existed at least as early as the Neolithic period. In the present era, almost half of the world's population consumes alcohol and it represents the third largest risk factor for disease and disability and the most prevalent cause of advanced liver disease worldwide. In fact, when alcohol consumption reaches "unsafe quantities" an Alcoholic Liver Disease (ALD) is very likely. ALD comprises a large spectrum of diseases, ranging from simple steatosis to steatohepatitis with fibrosis and cirrhosis. Alcohol related cirrhosis is responsible of almost 50% of all cirrhosis-related and 1% of all-cause deaths worldwide. Even if ALD and alcoholic cirrhosis represent a large part of liver diseases, to know exactly the global burden of these phenomena is very difficult. This is mostly due to diagnostic and nosological issues, being ALD represented by several types of diseases and the diagnosis very often based on voluntary questionnaires. Also the natural history of ALD is somewhat difficult to predict, since there is not a definite evolution between the various stages of the disease and, indeed, they may coexist in a single subject. In this brief review we will report on the global burden of ALD, the principal factors influencing its prevalence among populations and the different presentations of its natural history.